Mechanisms of localisation and function of metabotropic glutamate receptors regulated by the synaptic membrane protein ELFN

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K06568
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Nagasaki University
• Principal Investigator: MATSUNAGA Hayato 長崎大学, 医歯薬学総合研究科(医学系), 助教 (20437833)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: シナプス / 膜タンパク質 / GPCR / 代謝型グルタミン酸受容体

Outline of Final Research Achievements

The aim of this study is to elucidate the neuronal interrelationship between the Elfn of leucine-rich repeat transmembrane protein and the metabotropic glutamate receptor (mGluR) of class C GPCR. Elfn1 and 2 each interacts with specific mGluR. Elfn1 missense mutations found in patients with epilepsy and ADHD are in close proximity to multiple tyrosine phosphorylation sites. These phosphorylation sites are the target of two receptor tyrosine kinases, which induce Elfn1 internalization. Various missense and phosphorylation site mutants showd different endosome localization compared to wild-type Elfn1 and may be involved in determining the fate of Elfn1 for recycling to the plasma membrane or degradation. In the fear-conditioned memory and learning test, Elfn2 KO mice showed lower memory acquisition compared to the wild type. mGluR positive allosteric modulator administrated Elfn2 KO mice showed reduced recall of fear learning, whereas there was no significant effect in wild-type mice.

Free Research Field

機能生物化学

Academic Significance and Societal Importance of the Research Achievements

多数のゲノムワイド関連解析、家系解析、ミスセンス変異探索解析から、ロイシンリッチリピート型膜タンパク質は神経発達障害の遺伝的リスク要因となることが示されており、膜タンパク質群の機能変化に伴う神経回路網形成やシナプス成熟の不全が病態の中核の１つであると想定される。Elfnにより制御されるグルタミン酸神経系の調節異常とADHD様行動発症の機構を解明することは病態の理解につながるとともに、これまでの脳のドパミン量を増加させるADHD治療薬に加え、mGluRを標的とした新規治療薬の開発の有用な情報となることが期待される。